Various forms of inflammation are characterized by activation of macrophages. Macrophages are thought to induce and maintain inflammatory processes mainly by producing various products that, by acting on other cells, bring about the deleterious consequences of inflammation such as the generation of nitric oxide. For example, macrophages produce cytokines. These proteins are central mediators in inflammatory processes, such as the local inflammatory processes characteristic of arthritis or colitis. Cytokines produced by macrophages are also thought to be involved in systemic inflammatory processes, such as endotoxic shock. Macrophage products are more generally involved in pathophysiological mechanisms, such as plasma extravasation, inflammatory cell diapedesis, release of toxic free radicals such as nitric oxide, endothelial injury, and release of tissue degrading enzymes, which result in tissue injury and, ultimately, organ failure.
Tumor necrosis factor alpha (TNF-α) is a cytokine associated with macrophage activation. TNF-α is also thought to be involved in inducing most of the pathophysiological events characteristic of inflammation. TNF-α plays an important role in regulating inflammation, cellular immune response, and host defense. TNF-α is a key cytokine associated with the toxic effect of lipopolysaccharide (LPS) endotoxin and in the pathogenesis of septic shock, as evidenced by high serum plasma levels of TNF-α after LPS administration to animals or to human volunteers, or in septic subjects. Administration of anti-TNF-α antibodies protects against the lethal effects of LPS and of live bacteria in a variety of animal models. Moreover, TNF-α can be a central target in the treatment of rheumatoid arthritis. Conversely in diseases such as rheumatoid arthritis, osteoarthritis, psoriasis, Crohn's disease, inflammatory bowel disease and other chronic disorders of the immune system, excessive levels of TNF-α play a role in the pathophysiology. Indeed, blocking TNF-α can halt disease progression and has led to the search for inhibitors of TNF-α.
Interleukin-12 (IL-12) is another macrophage product that has been shown to be involved in the induction of pathology in several inflammatory diseases. These diseases include autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, insulin dependent diabetes mellitus, and rheumatoid arthritis, and inflammatory states such as septic shock and the generalized Schwarzman reaction.
Rheumatoid arthritis is a common rheumatic disease, affecting more than two million people in the United States alone. The disease is three times more prevalent in women as in men but afflicts all races equally. The disease can begin at any age, but most often starts between the ages of forty and sixty. In some families, multiple members can be affected, suggesting a genetic basis for the disorder. The cause of rheumatoid arthritis is unknown. It is suspected that certain infections or factors in the environment might trigger the immune system to attack the body's own tissues, resulting in inflammation in various organs of the body. Regardless of the exact trigger, the result is an immune system that is geared up to promote inflammation in the joints and occasionally other tissues of the body, Lymphocytes are activated and cytokines, such as TNF-α and interleukin-1 (IL-1) are expressed in the inflamed areas.
The clinical expression of rheumatoid arthritis is manifested by chronic inflammation of the joints, the tissue surrounding the joints such as the tendons, ligaments, and muscles, as well as other organs in the body such as the eyes. The inflammation process of causes swelling, pain stiffness, and redness in the joints. In some patients with rheumatoid arthritis, chronic inflammation leads to the destruction of the cartilage, bone and ligaments causing deformity of the joints. Rheumatic diseases can involve other, seemingly unrelated organs as well, such as eyes, skin and glands. Rheumatic diseases are usually divided into those that primarily involve joints, known as arthritis, and those involving other tissues, generally referred to connective tissue diseases. Arthritis is further subdivided into inflammatory and non-inflammatory arthritis. The more common types of inflammatory arthritis are rheumatoid arthritis, gout, psoriatic arthritis (associated with the skin condition psoriasis), reactive arthritis, viral or post-viral arthritis (occurring after an infection), and spondylarthritis which affects the spine as well as joints.